CF is an autosomal recessive disorder, the most common lethal genetic disease in Caucasians, (O'Sullivan 2009; Rowe, 2005; Accurso, 2006) characterized by chronic lung disease, the main cause of morbidity and mortality, pancreatic dysfunction, raised electrolyte levels in sweat, and male infertility. CF is caused by mutations of one single protein, the cystic fibrosis transmembrane conductance regulator (CFTR), a cAMP-regulated chloride channel that is primarily located at the apical membrane of epithelial cells (Park 2010). More than 1500 different disease-associated mutations have been identified, some of them encoding CFTR mutants reaching the cell plasma membrane but lacking CFTR activity, other ones encoding negligible amounts of protein or misfolded mutants that are prematurely degraded and fail to reach a cell surface localization. Among the latter, a single codon deletion, ΔF508, occurs in about 90% of CF patients on at least one allele. Due to its misfold, ΔF508-CFTR loses its essential ion channel activity at the plasma membrane (PM), thus provoking local inflammation, increased susceptibility to respiratory bacterial infections, and progressive pulmonary and digestive insufficiency (Collins 1992).
A still partially functional ΔF508-CFTR can be rescued at the plasma membrane (PM) by molecules that correct ΔF508-CFTR intracellular retention and degradation (correctors). However, ΔF508-CFTR that reaches the PM is unstable as result of a [carboxyl-terminus heat shock cognate 70 (Hsc70)-interacting protein] (CHIP)-mediated ubiquitination, followed by redirection of the protein from endosomal recycling towards lysosomal delivery and degradation (Okiyoneda T, 2010). Therefore, CF patients carrying the misfolded ΔF508-CFTR are poorly responsive to potentiators of CFTR channel activity that can be used for the treatment of the small subset of CF patients that carry PM-resident CFTR mutants (Ramsey B W, 2011; Davids P B, 2011). Therefore, fixing the misfolded ΔF508-CFTR mutant at the PM after rescue is the principal objective of “CFTR-repairing” therapies (Lucaks G L, 2012; Davids P B, 2011).
An ideal therapy for CF should aim not only at rescuing CFTR function, but also at ameliorating chronic lung inflammation and the increased susceptibility to bacterial infections that constitute the main clinical problem of CF patients (Belcher C N, 2010). A recent clinical trial with the CFTR corrector VX-809 in ΔF508-CFTR homozygous patients demonstrated modest dose-dependent reductions in sweat chloride (Clancy J P 2012; Elborn S. 2012). However, no improvement in lung function or CF complications was reported (Clancy J P 2012; Elborn S. 2012), and Phase II clinical studies combining VX-809 and the potentiator VX-770 have to be awaited to evaluate their clinical benefit.
We have reported that a complex derangement of protein homeostasis (proteostasis) occurs in CF epithelial cells and is caused by the loss of CFTR function. Increased levels of reactive oxygen species (ROS) induced by defective CFTR function lead to tissue transglutaminase (TG2) activation driving cross-linking and aggresome accumulation of several TG2-substrate proteins (Maiuri L, 2008; Luciani A, 2009), among which the sequestration of the essential autophagy protein Beclin-1 (Luciani A, 2010; Luciani A, 2011). The functional sequestration of Beclin 1 disloges the PI3K complex III away from the endoplasmic reticulum (ER), thus inhibiting autophagosome formation and driving inflammation in CF airways. This generates a feed forward loop that sustains oxidative stress and perpetrates inflammation. Defective autophagy was also confirmed in CF macrophages (Abdulrahman B A, 2012). Rescuing Beclin-1 and autophagy either by transfection-enforced Beclin 1 overexpression or by means of TG2 inhibitors (e.g. cystamine) or antioxidants (e.g. N-acetyl-cysteine or the superoxide dismutase (SOD)/catalase-mimetic EUK-134), blunts inflammation in ΔF508-CFTR homozygous airways, both in mice in vivo and in human tissues, in vitro (Luciani A, 2010; Luciani A, 2011). Moreover, rescuing autophagy favors ΔF508-CFTR trafficking to the plasma membrane of the epithelial cells.